DESCRIPTION: (Applicant's Description) Pre-clinical studies have demonstrated that tumor cells arrested in mitosis by Paclitaxel (Pac) and then radiated undergo enhanced radiation-induced tumor cell kill. To monitor the modulatory effects of Pac in patients receiving radiation (RT), we have developed methods to measure Pac-induced tumor cell mitotic arrest in human tumor samples. In an ongoing Phase I trial in head and neck squamous cell cancer (HNSCC) that combines a 24h infusion of Pac (Pac-24h) and RT, we observed biologically meaningful tumor cell mitotic arrest at the time of RT, excellent tumor responses, but excess hematological toxicity. Recently, the combination of a 3h infusion of Pac (Pac-3h) and RT was piloted in HNSCC. In order to optimize the use of Pac and RT (Pac/RT) in HNSCC, we believe it is essential to determine if differences in Pac schedule lead to biologically important differences in the degree of tumor cell mitotic arrest. Based on laboratory and clinical evidence, we hypothesize that Pac-24 induces greater tumor cell mitotic arrest than Pac-3h and is a superior Pac administration schedule for use in Pac/RT combination trials. In this proposal, we utilize the setting of resectable HNSCC to compare the tumor pharmacodynamic and toxicological effects of low dose Pac-24h and Pac-3h in combination with RT. In Specific Aim 1, laboratory correlative studies will be conducted prior to surgery to describe the lowest does of Pac-24h and Pac-3h that induces biologically meaningful tumor cell mitotic arrest (the Pac Modulatory Dose or PMD). In Specific Aim 2, we will describe the maximally tolerated dose (MTD) and dose-limiting toxicity (DLT) of weekly low-dose Pac-24h and Pac-3h combined with RT in the adjuvant setting. At the completion of the study, a comparison of the PMD and MTD within each Pac schedule will allow a more rationale approach to combining Pac and RT in the clinic.